Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Alternative Granulation Technique: Melt Granulation

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Scale-up feasibility in high-shear mixers: determination through statistical procedures

The wet granulation scale-up of a formulation exhibiting plastic deformation behavior under compression was examined. Through experimental factorial design, the effect of solution level, mixing time, and mixer speed on granulation properties was investigated. Measurements of mean particle size, tapped density, bulk density, Carr's index, coarse-to-fine ratio, cumulative percentage, and flow rate were taken and compared among granulations. In addition, comparisons were done on the hardness of tablets made from the formulations. It was shown that the characteristics of the granulations made under different conditions were highly reproducible. The excipient system of microcrystalline cellulose and pregel starch was shown to be a very robust formulation that is resistant to changes in the scaling-up process in high-shear mixers.     

Scale-up Feasibility in High-Shear Mixers: Determination Through Statistical Procedures

The wet granulation scale-up of a formulation exhibiting plastic deformation behavior under compression was examined. Through experimental factorial design, the effect of solution level, mixing time, and mixer speed on granulation properties was investigated. Measurements of mean particle size, tapped density, bulk density, Carr's index, coarse-to-fine ratio, cumulative percentage, and flow rate were taken and compared among granulations. In addition, comparisons were done on the hardness of tablets made from the formulations. It was shown that the characteristics of the granulations made under different conditions were highly reproducible. The excipient system of microcrystalline cellulose and pregel starch was shown to be a very robust formulation that is resistant to changes in the scaling-up process in high-shear mixers.     

Radon monitor calibration using NIST radon emanation standards: steady flow method

The National Institute of Standards and Technology (NIST) polyethylene-encapsulated 226Ra/222Rn emanation (PERE) standards (old SRM 4968 and new SRMs 4971, 4972, and 4973) provide precise radon emanation rate, certified to a high degree of accuracy (approximately to 2%). Two new SRM 4973 standards containing totally 1036 Bq (0.028 microCi) of 226Ra, emanate 0.114 Bq (3.08 pCi) of 222Rn per min. Air passing over such sources at a flow rate of 1 l min(-1) will have a radon concentration of 114 Bq m(-3) (3.08 pCi l(-1)). This paper describes a practical calibration system and the actual calibration verification data obtained at different flow rates, for E-PERM passive radon monitors, Femto-Tech and Alpha Guard Continuous Radon Monitors. The use of such an affordable and easy to use system by the manufacturers and users of radon measurement devices will bring uniform standards with traceability to a NIST standard source and is considered an important step in standardising radon measurement methods.     

Radon exhalation rate from the soil, sand and brick samples collected from NWFP and FATA, Pakistan

In order to characterise the building materials as an indoor radon source, knowledge of the radon exhalation rate from these materials is very important. In this regard, soil, sand and brick samples were collected from different places of the North West Frontier Province (NWFP) and Federally Administered Tribal Areas (FATA), Pakistan. The samples were processed and placed in plastic containers. NRPB radon dosemeters were installed in it at heights of 25 cm above the surface of the samples and containers were then hermetically sealed. After 40-80 d of exposure to radon, CR-39 detectors were removed from the dosemeter holders and etched in 25% NaOH at 80 degrees C for 16 h. From the measured radon concentration values, (222)Rn exhalation rates were determined. Exhalation rate form soil, sand and brick samples was found to vary from 114 +/- 11 to 416 +/- 9 mBq m(-2) h(-1), 205 +/- 16 to 291 +/- 13 mBq m(-2) h(-1) and 245 +/- 12 to 365 +/- 11 mBq m(-2) h(-1), respectively.     

Effect of Particle Size on Deformation and Compaction Characteristics of Ascorbic acid and Potassium Chloride: Neat and Granulated Drug

Abstract

Deformation and compaction characteristics of two soluble drugs, ascorbic acid and potassium chloride, were investigated. Five different particle size fractions of ascorbic acid with mean particle size (d₅₀) ranging from 30–300μm and four different particle size fractions of potassium chloride with d₅₀ ranging from 20–400 μm were selected in the study. The compaction behavior of the drug substances as neat drugs or as granulated drugs were evaluated on both a Carver press and an instrumented single-punch tablet press. The results clearly show that mean particle size of the drug substances plays an important role in their compactibility. Intrinsic compactibility of both drug substances was slightly improved with increased particle size. Granulations of the drugs with polyvinyl pyrrolidone significantly improved their compactibility. However, this effect was more pronounced in the drug substance with finer particle size. The Heckel plots indicate that deformation characteristics of both granulated drugs were related to their original mean particle sizes. The granulations prepared from the coarser particle size (d₅₀ 250 μm to 400 μm) underwent two stages of deformation, so-called “brittle fracture” and “plastic deformation”. While the granulations prepared from the finer particle size predoninantly underwent “plastic deformation”. The results indicated that the plastic deformation of both granulated drugs was progressively enhanced whilst fragmentation of particles was correspondingly reduced as the particle size of the drugs was decreased. Scanning electron photomicrographs indicated that the granulation process changed the surface morphology of the drug particles imparting more “microirregularities” or “defects”, thereby providing greater “interparticulate bonding” as compared with the neat drugs. Optimum particle size range of ascorbic acid and potassium chloride for satisfactory compactibility was found to be 30–40 μm and 20–40 μm, respectively. The present study demonstrates the importance of selecting the appropriate particle size of drug for the development of tablet dosage forms.     

Tableting Properties of Experimental and Commercially Available Lactose Granulations for Direct Compression

Abstract

Lactose granulations (125-250 μm) were prepared from two different β-lactose monohydrate powders and one roller dried B-lactose powder respectively, by wet granulation with only water as a binder. As an effect of the granulation process, the flow properties improved, but the compactibility decreased. Moreover, the lubricant sensitivity of the granule fractions was higher than found for the starting materials. The compactibility of the granule fractions was found to be dependent on the type of lactose, the surface area of the starting powder and the granule bulk density. For lubricated lactose granulations, the lubricant sensitivity, expressed as Lubricant Sensitivity Ratio (LSR), increased with an increase of bulk density. The β-lactose content of roller-dried β-lactose is hardly affected by the granulation process, which explains the good compactibility of the granule fractions prepared from this type of lactose. On the other hand, anhydrous α-lactose present in the roller-dried β-lactose starting material is converted into α-lactose monohydrate during the granulation process, which improves tablet disintegration.

The compaction properties of commercially available lactose granulations have been compared with those of the experimental granulations and with a free flowing sieved α-lactose monohydrate. As an effect of the higher powder surface area and the relatively low bulk density, Tablettose^R has a better compactibility than α-lactose monohydrate 100 Mesh. The excellent compactibility of another commercially available lactose granulation, Pharmatose^K DCL 15, was attributed to the presence of more β-lactose, providing strong intergra-nular cohesion.     

Effect of Particle Size on Deformation and Compaction Characteristics of Ascorbic acid and Potassium Chloride: Neat and Granulated Drug

Deformation and compaction characteristics of two soluble drugs, ascorbic acid and potassium chloride, were investigated. Five different particle size fractions of ascorbic acid with mean particle size (d₅₀) ranging from 30-300μm and four different particle size fractions of potassium chloride with d₅₀ ranging from 20-400 μm were selected in the study. The compaction behavior of the drug substances as neat drugs or as granulated drugs were evaluated on both a Carver press and an instrumented single-punch tablet press. The results clearly show that mean particle size of the drug substances plays an important role in their compactibility. Intrinsic compactibility of both drug substances was slightly improved with increased particle size. Granulations of the drugs with polyvinyl pyrrolidone significantly improved their compactibility. However, this effect was more pronounced in the drug substance with finer particle size. The Heckel plots indicate that deformation characteristics of both granulated drugs were related to their original mean particle sizes. The granulations prepared from the coarser particle size (d₅₀ 250 μm to 400 μm) underwent two stages of deformation, so-called “brittle fracture” and “plastic deformation”. While the granulations prepared from the finer particle size predoninantly underwent “plastic deformation”. The results indicated that the plastic deformation of both granulated drugs was progressively enhanced whilst fragmentation of particles was correspondingly reduced as the particle size of the drugs was decreased. Scanning electron photomicrographs indicated that the granulation process changed the surface morphology of the drug particles imparting more “microirregularities” or “defects”, thereby providing greater “interparticulate bonding” as compared with the neat drugs. Optimum particle size range of ascorbic acid and potassium chloride for satisfactory compactibility was found to be 30-40 μm and 20-40 μm, respectively. The present study demonstrates the importance of selecting the appropriate particle size of drug for the development of tablet dosage forms.     

Radon diffusion coefficients in 360 waterproof materials of different chemical composition

This paper summarises the results of radon diffusion coefficient measurements in 360 common waterproof materials available throughout Europe. The materials were grouped into 26 categories according to their chemical composition. It was found that the diffusion coefficients of materials used for protecting houses against radon vary within eight orders from 10(-15) to 10(-8) m(2) s(-1). The lowest values were obtained for bitumen membranes with an Al carrier film and for ethylene vinyl acetate membranes. The highest radon diffusion coefficient values were discovered for sodium bentonite membranes, rubber membranes made of ethylene propylene diene monomer and polymer cement coatings. The radon diffusion coefficients for waterproofings widely used for protecting houses, i.e. flexible polyvinyl chloride, high-, low-density polyethylene, polypropylene and bitumen membranes, vary in the range from 3 × 10(-12) to 3 × 10(-11) m(2) s(-1). Tests were performed which confirmed that the radon diffusion coefficient is also an effective tool for verifying the air-tightness of joints.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile than was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile that was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

Abstract

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile that was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

Abstract

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile than was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Suppression methods of radon emanation from phosphorus fertiliser and diatomaceous earth

The present paper shows methods to suppress radon emanation from artificial porous materials such as phosphorous fertiliser or diatomaceous earth with a small amount of radium. The basic concept of suppression is making the radon emanation mechanism 'null', which comes from the fact that recoil is the main mechanism of radon emanation at room temperature. Nullifying may be done through removal of water in the pore volume by heating and through removal of pores by melting or filling with sulphur. These radon emanation suppression methods were tried for phosphorous fertiliser and diatomaceous earth with a small amount of radium. The melting method was the most effective of all. Sustainability of these methods was also studied. The melting method was the most sustainable. The heating method was also sustainable for diatomaceous earth in spite of a long-term immersion in water.     

Radon measurement in schools located in three priority investigation areas in the province of Quebec, Canada

The purpose of this study was to measure radon concentration in public primary schools located in priority investigation areas, with the aim of decreasing occupants' exposure to radon in public buildings where concentrations exceed the Canadian Federal guidelines (i.e. 200 Bq m(-3)). In addition, the association between radon levels, substratum geological characteristics and schools' structural characteristics were investigated. The results showed that radon concentrations measured in the 65 investigated schools are generally below the Federal guideline levels. Eleven schools (17 %) had at least one measurement above the Federal guideline, while one had a level above 600 Bq m(-3). On average, targeted schools' occupants are exposed to radon concentrations of 56 Bq m(-3). Although statistical analysis, which was limited by the sample size, did not show any link between aggregated radon measurements and geochemical or radiological signatures of investigated sites, the geological evidence that led to the choice of the studied regions remains relevant.     

Thermal diffusion of radon in porous media

Based on the non-intersection model of cylindrical capillaries, the mean radius of the pores of some soils and building materials are estimated. In size, the above-mentioned radii are usually of the order of the free path of gas molecules at atmospheric pressure. A review of pore size distribution data also reveals that a large fraction of concrete pores belong to Knudsen's region. This fact indicates that the thermal gradient in these media must cause gas (radon) transport. The interpretation of the experimental data concerning the rate of emanation of 222Rn from a concrete-capped source subjected to a sudden increase in temperature is given, based on irreversible thermodynamics theory. The calculations given here for radon flux, caused by concentration and thermal gradients, are in satisfactory agreement with the experimental data. It is shown that thermodiffusion can significantly contribute to radon flux in concrete. The need to include the thermodiffusion radon flux in the radon entry model is discussed.     

Natural radionuclides contents and radon exhalation rates in building materials used in South Korea

The natural radionuclide (226Ra, 232Th and 40K) contents of building materials commonly used in South Korea have been determined by a gamma ray spectroscopy system using a high purity germanium detector. The radon exhalation rates and emanation coefficients of building materials have also been studied. The average concentrations of 226Ra, 232Th and 40K in building materials were in the range of 6.47-271 Bq.kg-1, N.D.-89.9 Bq.kg-1 and 16.8-1081 Bq.kg-1, respectively. The average radon exhalation rates and emanation coefficients were in the range of 0.0061-0.2404 Bq.kg-1.h-1 and 2.39-11.5%, respectively.     

Radon progeny size distributions and enhanced deposition effects from high radon concentrations in an enclosed chamber

Prior work studying radon progeny in a small enclosed chamber found that at high (222)Rn concentrations an enhanced surface deposition was observed. Subsequent measurements for unfiltered air showed minimal charged particle mobility influence. Progeny particle size measurements reported here, performed at the US Department of Energy Environmental Measurement Laboratory (now with Home Security Department), using the EML graded screen array (GSA) system show in unfiltered air that the high (222)Rn levels causes a reduction in the attached (218)Po progeny airborne particulates and formation of additional normal sized unattached ( approximately 0.80 nm) and also even smaller (218)Po below 0.50 nm. At a (222)Rn level of 51 kBq m(-3), 73% of all (218)Po are of a mean particle diameter of about 0.40 +/- 0.02 nm. At this (222)Rn level, the ratio of (218)Po to (222)Rn airborne concentrations is reduced significantly from the concentration ratio at low (222)Rn levels. Similar reductions and size reformations were observed for the (214)Pb and (214)Bi/Po progeny. The particle size changes are further confirmed using the plateout rates and corresponding deposition velocities. The Crump and Seinfeld deposition theory provides the corresponding particle diffusion coefficients. With the diffusion coefficient to ultrafine clustered particle diameter correlation of Ramamurthi and Hopke, good agreement is obtained between EML GSA and deposition velocity data down to 0.40 nm. Strong evidence is presented that the progeny size reduction is due to, as a result of air ionization, the increased neutralization rate (primarily from electron scavenging of OH molecules) of the initially charged progeny. This is shown to increase with the (1/2) power of (222)Rn concentration and relative humidity as well as increased air change rate in the chamber. These results imply that at (222)Rn levels above 50 kBq m(-3), at relative humidity of 52%, a considerable reduction in lung dose could occur from preferential deposition of the progeny in the nasal and oral passages.     

矿化剂氟化锂对镨锆黄陶瓷色料的影响

谱锆黄陶瓷色料由于呈色稳定,价格较低廉已成为高温陶瓷色料市场的宠儿,但传统固相法所制备的谱锆黄陶瓷色料煅烧温度高(1 600℃),导致颜料粒径过大影响呈色性能,因此,降低合成温度减小粒径已成为这一方向的研究的热点.本文利用八水合氧氯化锆、正硅酸乙酯、稀土氧化镨为主要原料,采用溶剂热法制备镨锆黄粉体颜料前驱体,加入不同含量的矿化剂氟化锂(LiF)以降低合成温度,对其在1 100℃煅烧,保温50 min获得镨锆黄陶瓷粉体颜料.采用色度分析仪、粒度分析仪、紫外可见光光谱分析仪、扫描电镜和X射线衍射分析技术对样品结构和性能进行表征.实验结果表明:当矿化剂LiF含量为0.35%时,样品中的ZrSiO_4结晶度较高,颗粒尺寸分布较小且较均匀,样品在400~480 nm蓝紫光有非常强的吸收,呈现较纯正的黄色色调,其色度值为L~*=84.92,a~*=4.70,b~*=68.00.该谱锆黄陶瓷色料可望应用于陶瓷喷墨打印技术领域.